Diabetes mellitus is a disorder of glucose regulation with accumulation of glucose in the blood. In normal individuals, insulin is secreted basally, usually in the range of 0.5 to 1.0 units per hour, and the levels are increased after a meal. Responsive to the rise in blood glucose levels following a meal, the pancreas secretes a bolus of insulin, which returns blood glucose to normal levels by stimulating the uptake of glucose into cells and signaling the liver to reduce glucose production. There are normally two phases of insulin release in response to a meal. The early phase (responsible for shutting down hepatic glucose production) is a spike of insulin release that occurs within 2-15 minutes of eating. The late phase release extends about 2 hours. Between meals the liver breaks down glycogen stores to provide glucose to the brain and other tissues.
Diabetes results in chronic hyperglycemia due to the inability or reduced ability of the pancreas to produce adequate amounts of insulin or due to the inability or reduced ability of cells to synthesize and/or release insulin. In diabetics, the effectiveness of the first-phase response is decreased or absent, leading to elevated postprandial glucose levels. Diabetes is a major public health problem affecting 285 million people across the world and this number is expected to be over 450 million by 2030 (Wild, et al., Diabetes Care, 27: 1047-1053 (2004). The malfunction of glucose regulation arises from (1) insufficient secretion of insulin due to autoimmune-mediated destruction of pancreatic f3-cells (type 1 diabetes) or (2) disorders of both insulin resistance and secretion (type 2 diabetes) (Pickup, et al., Diabetes Metab. Res. Rev., 24: 604-610 (2008); Stumvoll, et al. Lancet, 365:1333-1346 (2005); and Kahn, Diabetes 43:1066-1084 (1994).
Frequent subcutaneous insulin injections and regular monitoring of blood glucose levels are essential for treatment of type 1 diabetic patients and some type 2 diabetic patients (Owens, et al., Lancet, 358:739-746 (2001)). However, such self-administration is painful and requires an indispensable commitment of patients. More importantly, this treatment, known as open-loop insulin delivery, does not maintain normoglycemia due to highly dynamic blood glucose concentrations (Jeandidier, et al., Adv. Drug Deliv. Rev., 35:179-198 (1999); Owens, et al., Nat. Rev. Drug Discov., 1:529-540 (2002)). Lack of tight control over glucose concentrations closer to the normal level accounts for many chronic complications such as limb amputation, blindness and kidney failure and can result in fatal hypoglycemia (N Engl J Med., 329:977-986 (1993)). Therefore, a pancreas-like, synthetic closed-loop device able to continuously and intelligently release insulin in response to blood glucose levels is highly desirable (Kumareswaran, et al. Expert Rev. Med. Devices, 6:401-410 (2009); Ravaine, et al., J. Control Release, 132:2-11 (2008)).
A straightforward strategy to achieve continuous release in response to glucose levels is to integrate a glucose monitoring moiety and a sensor-triggered insulin releasing moiety into one system. To date, a number of glucose-responsive formulations and devices have been explored, mainly derived from three categories: (1) glucose oxidase (GOx) based enzymatic reaction-induced response systems; (2) binding lectin protein Concanavalin A (Con A) based response systems, and (3) phenylboronic acid (PBA) based synthetic glucose-binding systems (Ravaine, et al., J. Control Release 132:2-11 (2008)).
Efforts to prepare insulin with patient-specific kinetics have explored a number of different modification strategies to create variants with more rapid activity as well as those with prolonged activity, and combinations of various types may be useful for improved glycemic control. For comparison, native insulin, which forms hexamers when formulated with zinc, has an onset time of 30-60 minutes, a peak window of action from 2-3 hours, and a duration of action of 8-10 hours. Fast acting formulations have been developed, such as Insulin Lispro where the B29 lysine residue and the B28 proline residue have been switched, in order to prevent hexamer formation and improve uptake. Lispro has a reduced onset time of just 5-15 minutes, with its a peak action at 30-90 minutes and a duration of action of 4-6 hours. Long acting formulations, such as Insulin Detemir where a saturated fourteen-carbon alkyl segment is covalently attached to the amine side-chain of lysine B29, have been developed to prolong insulin duration by enabling it to bind to and be sequestered by circulating serum albumin. As a result, Insulin Detemir has an onset of action at 1-2 hours, with peak action at 6-8 hours and duration lasting up to 24 hours. Long acting insulin, in particular, is useful as a daily injection to supplement basal insulin levels and prevent spikes in blood glucose levels throughout the day.
PBA is boronic acid containing a phenyl substituent and two hydroxyl groups attached to boron. PBA and its derivatives form complexes with polyol molecules such as glucose and fructose, and can form complexes with polyols and diols. The ability of PBA to bind polyols and diols has been exploited in different ways to provide a glucose binding insulin delivery system. Some researchers have directly coupled a PBA moiety to insulin, to provide glucose binding insulin. For example, U.S. Publication No. 20030186846 by Hoeg-Johnson, et al., discloses an insulin delivery system made of insulin derivatives with a built in glucose sensor, such as an aryl boronate moiety.
These glucose insulin delivery systems have several limitations. For PBA systems, the challenge remains to design devices that function in response to glucose under physiological conditions.
It is therefore an object of this invention to provide a non-toxic, interactive or “smart” insulin delivery system that is responsive to changing glucose concentrations.
It is a further objection of the present invention to provide a method of controlling blood glucose levels in a patient in need thereof, by administering a smart insulin delivery system which responds to changing glucose concentrations.